Exam 1 Flashcards
Pharmacodynamics?
What the drug does to the body
Pharmacokinetics?
What the body does to the drug
Agonist?
Binds to receptor and elicits an effect downstream
Antagonist?
Binds to receptors & inhibits effect of agonist
(does not increase or decrease agonist)
Endogenous agonist?
Naturally product in the body.
Ex: Dopamine
Orphan receptor?
Endogenous ligand. Don’t know what it binds to or does.
Poisons?
From Non-living Ex: Arsenic, lead
Toxins?
From Living organisms Ex: pufferfish, Botox
Problem with drugs >1,000MW?
Difficulty crossing barrier & excreting
What must drugs have to bind to receptor?
Right size, charge, shape, atomic composition
Strongest bond?
Covalent bond, usually irreversible
Orthosteric receptors?
Active site, where native ligand binds
Allosteric receptor?
Binding elsewhere on the receptor(protein), are non-competitive, can change the shape of different receptor site. Activating or inactivating it.
What is Ec50?
50% effect of the drug
What is Kd?
50% of receptors are bound by the drug.
What does Low Kd mean?
High receptor affinity. Ex: Covalent bond= low Kd
What do an agonist & allosteric activator create & Example?
A synergystic effect- max effectiveness w/ less drug. Ex: Morphine & phenergan
What if an agonist & competitive inhibitor mix?
More agonist needed to produce effect.
What is an agonist mimic?
Indirect agonist- doesn’t act at receptor & prolongs effect.
Blocks enzyme that breaks down downstream effect.
Example of Charge Antagonism?
Protamine (+) binds to and inhibits Heparin (-).
Physiologic antagonism?
Drugs act at different receptors to squelch effect of other drugs. Cause opposite effect.
Ex: one drug increase HR & one drug decrease HR.
Proteins favor what kind of receptor?
Inactive form
Drugs favor what kind of receptor?
Active receptors
what does an Inverse agonist do?
Higher affinity to the inactive form, acts as an antagonist to keep receptor inactive and/or
causes opposite effects produced by conventional agonist at the receptor.
What is Potency?
Concentration of drug (ED50) needed for 50% of the drug’s effect.
What is Max efficacy?
Greatest possible response a drug can deliver
Depends on interaction with receptor
Clinical effectiveness?
Max effect, not max potency
What does ED50 mean?
Effective dose=50% of population have the benefit from the drug.
What is TD50?
Toxic dose=50% of population have toxic effect.
What is Therapeutic Index and how is it calculated?
TD/ED= calculates the safety of the drug
What is tachyphylaxis?
Quick tolerance
What are exogenous receptors?
Receptor activated by external compounds
Describe the relative bond strengths
1: Covalent bond= strongest bond
2: Electrostatic (charged molecules, H+ bonds, Van Der Waals forces)
3: Hydrophobic- Lipid soluble forces
Discuss the four main causes of drug variation.
1: Alteration in concentration that reaches receptors
- Age, weight, sex, disease state, rate of absorption, clearance
2: Variation in concentration of endogenous receptor ligand
3: Alteration in number or function of receptors
4: Changes in components of response distal to receptor
- Post receptor process, body compensation, largest & most important cause
What is Toxicology?
- Study of toxins & poisons
- Undesirable effect of chemicals on living systems
Pharmacogenomics?
How genetic makeup affects the drug response
Distinguish between a competitive inhibitor and an allosteric inhibitor.
1: Competitive inhibitor: molecule that binds to active receptor site
2: allosteric inhibitor: Binds to enzyme/receptor surface changing active receptor site.
Describe physiologic antagonism.
Behavior of a substance that produces effects counteracting those of another substance using a mechanism that does not involve binding to the same receptor.
Describe the role of drug carriers, and list the most common ones in the blood.
Albumin: Binds most acidic drugs
Alpha1-acid glycoprotein: binds most basic drugs
Lipoproteins binds most neutral drugs
Describe the following term: partial agonist
Partial agonist: bind-to and activate a given receptor, but have only partial efficacy at the receptor.
Describe inverse agonist.
Ligand that binds to the same receptor-binding site as an agonist and not only antagonizes the effects of an agonist but, moreover, exerts the opposite effect by suppressing spontaneous receptor signaling
Define racemic mixtures, and correlate stereoisomerism and differences in drug effects.
Example?
A 50/50 mixture of two enantiomers(mirror image of a drug).
Example: Ketamine (S)= 4x more potent & (R)= more toxic.
Explain all 4
A= Agonist alone
A+C= Synergistic effect- max effect with less drug
A+B= More agonist needed to outcompete B to produce same effect
A+D= insurmountable, non-competitive= allosteric inhibitor
What are ligands?
Molecules that bind to receptor sites.
Define receptor
a cell or group of cells that receives stimuli. : a chemical group or molecule (such as a protein) on the cell surface or in the cell interior that has an affinity for a specific chemical group, molecule, or virus
Compare the efficacy and the potency of 2 drugs on the basis of their graded dose-response curves.
- B is the most potent drug.
- A, C, D have equal efficacy but A is more potent out of A, C, D
Describe “trapping” of a drug.
Alter the pH of urine to change the charge to trap it in the urine.
- Acidic drugs are excreted faster in alkaline urine.
- Basic drugs are excreted faster in acidic urine.
Evaluate how a partial agonist can also be an antagonist.
A partial agonist blocks the full agonist’s receptors and only exerts a fraction of the desired effect.
Describe Noncompetitive Inhibition.
Example
An agonist is given or naturally produced, then an antagonist is given, which bonds stronger to receptor (Ex: Covalent bond), & agonist cannot outcompete antagonist no matter how much agonist is given.
Ex: Norepinephrine(agonist) to increase BP the Phenoxybenzamine(antagonist). Norepinephrine is unable to outcompete Phenoxybenzamine due to its covalent bond.
Explain Kd not equal EC50.
Kd= (concentration at which 1/2 of receptors are bound): largely depends on the drug structure, specific receptor, bonding type.
EC50(50% of the drug’s effect): depends on the downstream effects in the body.
Explain specific binding & non-specific binding.
Specific binding is a drug binding to its designated receptor.
Non-specific binding happens once all specific receptors are saturated and binds somewhere else.
Ex: Excess drug binds to albumin.
What are these drug classes.
- vir
-cillin
cef-
- vir= antiviral (aciclovir)
-cillin= PCN derived Abx (PCN)
cef- = Cephem-type Abx (cefazolin)
Drug classes
-mab
-ximab
-zumab
-mab= Monoclonal antibodies (trastuzumab)
-ximab= Chimeric antiobody (infliximab)
-zumab= humanized antibody (natalizumab)
Drug classes
-tinib
-vastatin
-prazole
-tinib= Tyrosine-kinase inhibitor (erlotinib)
-vastatin= HMG-CoA reductase inhibitor (atorvastatin)
-prazole= Proton-pump inhibitor (omeprazole)
Drug classes
-lukast
-grel-
-axine
-lukast= Leukotriene receptor antagonist (Montelukast)
-grel-= Platelet aggregation inhibitor (clopidrogel)
-axine= Dopamine & sertotonin-norepinephrine reuptake inhibitor(venlafaxine)
Drug classes
-oxetine
-sartan
-oxacin
-oxetine= Antidepressant related to fluoxetine (duloxetine)
-sartan= Angiotensin receptor antagonist (losartan)
-oxacin= Quinolone-dereived antibiotics (levofloxacin)
Drug classes
-barb-
-xaban
-afil
-prost
-barb-= Barbiturates (Phenobarbital)
-xaban= Direct Xa inhibitor (apixaban)
-afil= Inhibitor of PDE5 w/ vasodilator action (sildenafil)
-prost= Prostaglandin analogue (latanoprost)
Name 3 characteristics of Albumin
1) most abundant carrier
2) has 2 binding sites
3) Most acidic drugs bind to it
Name an example for tachypylaxis
Nitric oxide
What is an idiosyncratic drug response
An usual/out of the norm response
What do drugs need to be to cross barriers?
Need to be uncharged
Does an acid compound release or gain a H+ when in a solution?
Releases
Does a Base absorb or release a H+ when in a solution?
Absorbs
If an acid w/ pKa of 3.5 is in the stomach (pH= 1.5) then what is it?
(two things)
Protonated & Uncharged
If a Base w/ pKa of 8 is in the stomach (pH=1.5) then what is it?
(two things)
Protonated & Charged
Where are most drugs filtered?
At the glomerulus
If there is an uncharged drug in urine what is most likely to happen?
Most likely will go back into the bloodstream
How do Ligand-gated channels work?
Open when something binds to them
How do Ion channels work?
- Open when something binds to them or there is a voltage change.
- Some are always open
Where are nuclear receptors?
Only found in the Nucleus
What is an Effector?
A protein that causes the desired effect downstream
What is a lag period?
1) Can be a growth factor.
2) Requires transcription/translation.
3) Response seen in 30mins to several hours.
Explain persistence
- Protein degradation pathways vary
- Response remains for hours to days
- Made proteins remain in system & drug might not be anymore
What is Pleiotropy?
Several downstream effects.
What does a G-Protein look like?
- Trimeric- ⍺, β, ɣ
- Inactive form is called GDP
- Active form is called GTP
What is & explain the steps of a phosphorylation cascade?
- Amplifies the signal.
1) Signal molecule binds to receptor
2) Creating a activated relay molecule/protein
3) Relay molecule activates inactive protein kinase (kinase=enzymes that
attaches a phosphate group to another protein)
4) The protein kinase activates another or multiple & so on
5) Eventually get to Effector protein to elicit cell response
6) Continues until signal molecule decouples from receptor or run out of relay
molecule or proteins
What are Intracellular receptors?
Can only be activated by something that can cross membrane(non-charged, cortisol, lipid-soluble, gasses)
What are Catalytic cell surface receptors?
set up an enzymatic reaction( convert 1 molecule into another) / phosphorylation
Explain Tyrosine kinase receptors
- Has tyrosine inside the cell & becomes active when phosphorylated.
- Usually for growth factors & adhesion.
- Two receptor tyrosine kinase on the surface called homo-dimers.
- When they join they form the active form of receptor= Dimerization.
- ATP comes in and phosphorylates the tyrosine
- Relay proteins come in (can be different ones)
- They take active TK and perform cell function
What is dimerization?
When two receptors sites join together to form an active receptor
Name 3 things about Voltage Gated-Channels
- Closed at rest
- Change shape depending on change in voltage
- Very large proteins
What is an Ionotropic Ligand-gated Ion channel?
- Ligand binding site & channel on same protein
- Ligand binds and same protein opens its channel
Ex: naCH receptor
What is a Metabotropic Ligand-Gated Ion channel?
- 2 channels in 1 (GPCR & Ion channel)
- Ligand binds to receptor & activates G-protein, which activates secondary messenger, which then activates the opening of an Ion channel.
Ex: Odor receptor
Receptors Inside Cell are for what?
Example?
- For Gasses & Lipid Soluble Agents
- Ex: Nitric oxide diffuses into smooth muscle cell activate GC, which turns GTP
into cGMP-> smooth muscle relaxation
Explain GPCR Desensitization & the 2 ending options.
1) GTP & ⍺ are gone leaving only the β & ɣ units.
2) β, ɣ recruit β arrestin receptor kinase(β ARK).
3) (β ARK) phosphorylates the GPCR.
4) The Phos groups attract β-arrestin.
5) The β-arrestin coupled GPCR pulls the receptor into
the cell(Clathrin pit) called endocytosis.
6) Once inside the cell β-arrestin decouples from receptor.
7a) GPCR is degraded via lysosomes.
7b) GPCR is dephosphorylated & resensitazied via peroxisomes.
Explain GPCR Activation cascade
- Ligand binds to receptor & changes/activates receptor
- G-Protein is attracted
- GDP released and GTP attached to G-Protein
- GTP & ⍺ separate from β, ɣ and attach to an inactive enzyme
- This enzymes becomes active for desired effect
Or - This enzymes cuts out the phos, turning GTP back into GDP
- The enzyme uses ATP & turns it into a secondary messenger like cAMP or
(gGMP, Calcium, DAG, IP₃) - cAMP activates/phosphorylates pkA (protein kinase A)
- The pkA now phosphorylates various proteins(Effectors) for desired effect.
Draw a phosphorylation cascade (generic).
Describe drug biotransformation and the difference between a prodrug and an active drug.
- Drug is affected by the body/enzymes.
- Pro drug: Gets converted from inactive form to active form.
- Active drugs: Are ready to go and become inactive after metabolic reactions.
Describe the first pass effect, and the route of an oral drug through the liver.
- Blood goes from intestinal tract to the portal vein. PO drugs.
GI —> local veins —> hepatic portal vein —> Sinusoids —> Hepatic vein—> Vena cava—> Systemic - Sinusoids: Have mixed blood. Bad in CHF.
- Hepatocytes: Absorb drug & get rid of it, do nothing, or transform it.
List the major phase I and phase II metabolic reactions.
Phase I:
- Change the drug slightly in order to make it more water soluble.
- Adding an OH group or unmasks drug to ease reaction.
- Hydrophobic to hydrophilic.
Phase II:
- Conjugation reaction (add a large structure like sulfate group or glucose).
Often detoxifying.
- Larger drugs won’t cross barriers and stay in urine.
- Lipophilic to hydrophilic.
Know which P450 isoforms (3) are responsible for the greatest number of important reactions.
CYP2B6, CYP2D6, CYP3A4.
CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, CYP3A4, CYP3A5
What is a Redux reaction?
- Something gets oxidized, something gets reduced.
- Oxidation is a loss of electrons.
- Reduction is a gain of electrons.
Delineate the generic pathway of CYP450 metabolism.
Drug X(lipophilic) has a Hydrogen —> comes into liver —> binds to CYP450 —> oxidation reduction reactions —> drug has now OH group —> released & is now more hydrophilic.
Define what is meant by “wild type” CYP enzymes, and how they are notated.
- CYP1 is the most common & called “wild type”
- Polymorphic variants are designated with an . Ex: CYP1A2
- They have a variance in their structure
Describe the mechanism of hepatic enzyme induction and inhibition.
Some drugs enhance synthesis, some inhibit degradation of P450.
Induction:
- P450 Inducer enhances ProDrug conversion to its active form.
Inhibition: Decrease or irreversibly inhibit P450
- P450 Inhibitor decreases P450 enzyme that degrades active drug to inactive form.
- P450 inhibitor inhibits or decreases ProDrug conversion to active form.
List the pharmacokinetic variables (ADME).
Absorption / Distribution / Metabolism / Excretion
Describe the four ways a drug gets across barriers.
- Aqueous diffusion: drug thru pore. For small molecules, charged drugs
- Lipid diffusion: Non-charged & lipid soluble
- Special carriers: Larger drugs or highly charged
- Endocytosis & Exocytosis: Cell swallows drug & cell expels drug out of cell
Define Volume of distribution (Vd), Clearance (CL), Concentration (C), Rate of Elimination (ROE), Target concentration (TC), Half-life (T1/2), and Bioavailability (F).
- Vd: Space available in the body to contain the drug. If drug stays in blood then
can estimate correctly.
Where is the drug going in the body. Adipose tissue? Fat vs skinny ppl. - CL: Ability of the body to eliminate the drug. How fast body can get rid of the
drug based on concentration. Clearance is constant for most drugs. - C: Concentration in blood (Cb) vs Concentration in Plasma (Cp) vs
Concentration in water (unbound drug Cu). - RoE: How fast body gets rid of drug. Tied to clearance.
- TC: Concentration we would want in the blood that will produce desired
effect. - T1/2: Time required to change drug in body to 1/2 of its concentration. After 4
1/2 lives no more effect.
Can be affected by disease states & distribution into varies tissues. - F: How much of the drug reaches systemic circulation based on route of
administration.
IV: 100%
IM, transdermal & SC: ~ 75 to <100%
PO: ~ 5 to < 100%
Relate Vd and CL to drugs (what is meant by a high Vd? a high CL?)
- High volume distribution(Vd) drug won’t stay in blood & distribute throughout the body.
- Low volume distribution(Vd) drug usually stays in blood. (5-10L)
Define capacity limited elimination and the variables in the equation.
- Same as Zero-order elimination. Dependent on concentration. Starts as 1st order —> turns into zero-order
- Capacity of receptors that bind to drug is limited.
Vmax: Max elimination capacity. - Km: Drug concentration where elimination is 1/2 Vmax.
Analyze flow dependent elimination as it relates to extraction ratio.
- Some drugs are highly sensitive to first pass metabolism as the liver, lung, or kidneys may remove high amounts of the drug. This depends on the individual’s blood flow.
- A low extraction ratio means the drug will pass through the system multiple times.
- High Extraction ratio + High Blood Flow= High Clearance
- High Extraction ratio + Low Blood flow= Low clearance
Describe the blood level versus time for drugs subject to zero-order elimination and for drugs subject to first-order elimination. What remains constant (CL, or ROE)?
- First-order: Clearance is constant, rate of elimination varies w/ concentration.
- Zero-order: Rate of elimination is constant, clearance varies w/concentration.
- All transporters getting rid of drug being used.
- As drug concentration increases, the amount of drug elimination per
hour does not increase.
- Ex: Phenytoin, ethanol, Fluoxetine, Omeprazole
When does drug accumulation occur?
If dosing interval is shorter than four half-lives, accumulation is detectable.
Factors(6) affecting Bioavailability?
- Physical properties of the drug (hydrophilic, solubility, pKa, etc)
- Formulation & route
- Interactions w/ other drugs
- GI- diet, gastric emptying, transporters
- Overall health / disease state
- Circadian rhythm
List 7 routes of drug administration.
IV, IM, SC, PO, inhalation, rectal, transdermal
Describe Therapeutic Drug Monitoring (Peak and trough).
- Peak: 5-10mins after IV administration
- Trough: Drawn 30mins prior to next dose
- Clearance is the single most important factor.
- Blood flow, albumin concentration.
List the test used to determine kidney function.
Creatinine Clearance
What is the calculation for ideal body weight and when is it used for drugs?
- When drugs have a low Vd.
- Men= 52 + (1.9kg x inches over 5 feet)
- Women= 49 + (1.7kg x inches over 5 feet)
Explain how Tyrosine Kinase receptor operate.
What are they often used for?
- Often for Growth factors & adhesion
- 2 signal molecules bind to receptor—> forms dimer—> dimer activates itself—> ATP comes in & phosphorylates the tyrosine—>activate secondary messengers.
Describe the role of second messengers, and list the most common as described in lecture.
- Activate intracellular signaling pathways that amplify the signal or inhibition of transcription factors
- cAMP, cGMP, Calcium, DAG, IP₃
Elucidate the mechanism of GPCR signaling.
- Ligand bind to receptor—> conformational change—> G-protein becomes active(GTP comes in)—> ⍺ sub-unit dissociates—> activates downstream effects.
- Another ⍺ sub-unit can come in and start over again.
Define the structure of GPCRs including their components.
- Seven trans-membrane ⍺-helics
- Trimeric: ⍺, β, ɣ
- GDP (inactive) —> GTP (active)
Name 4 transmembrane signaling methods by which drug-receptor interactions exert their effects.
- Intracellular receptors: Drug has to cross membrane (lipid soluble, gas, non-
charged, cortisol, chol). - Ion channels: Binds & opens an Ion channel
- Catalytic: Drug binds & sets up a cascade or enzymatic change.
Ex: Tyrosine kinase - GPCRs: G-Protein activated
What is a phosphates?
Subtracts a phosphate from a protein & turns protein to inactive form.
What is a kinase:
An enzyme that catalyzes the transfer of a phosphate group from ATP to a protein.
Describe the cell signaling process.
- Signaling cell releases the signaling molecule.
- Molecule attaches to active cell-surface receptor.
- Signal transduction proteins & secondary messengers relay the message to
Effector proteins - Effector goes to perform its function (metabolism, movement, gene
expression, etc).
List receptor type (7) based on molecular structure.
- GPCRs (Seven-transmembrane (7TM) receptors
- Ligand-gated channels: Open when ligand binds
- Ion channels: Open if Voltage change or when ligand binds
- Catalytic receptors: Enzymatic reaction occurs when something binds
Ex: tyrosine kinase - Nuclear receptors: Inside the nucleus.
- Transporters: Transport large bulky items in & out
- Enzymes
What are the volumes of whole blood and plasma in the body for a 70Kg person?
- Whole blood: 0.08 L/Kg
- Plasma: 0.04 L/Kg
Describe the relative bond strengths.
- Covalent 50-150 kcal/mol
- Ionic 5-10 kcal/mol
- Hydrogen 2-5 kcal/mol
- Hydrophobic 0.5-1 kcal/mol
Chemical antagonist
Drugs combine to produce an inactive form.
Rational Dosing?
Goal is to achieve desired beneficial effect with minimal adverse effects
What are the 4 protein configurations?
- Regulatory proteins
- Enzymes
- Transport proteins
- Structural proteins
